ジュベール症候群関連疾患

Biallelic variants in a family with sequence similarity 149 member B1 gene (FAM149B1, OMIM #618413) causes a range of abnormal phenotypes associated with Joubert syndrome (JS) in humans. However, the phenotypic spectrum and genetic evidence linking FAM149B1 to ciliopathies remain limited, with no prenatal cases previously described. Here, we report the first prenatal case from a non-consanguineous Chinese family presenting with isolated right pelvicalyceal and ureteral dilation at 24 weeks of gestation. Notably, the fetus lacked cerebellar malformations or hallmark neuroimaging features such as molar tooth sign (MTS). Trio-whole-exome sequencing (Trio-WES) identified novel compound heterozygous loss-of-function variants in FAM149B1: paternal c.279T>A (p.Tyr93*) and maternal c.574dup (p.Ser192Phefs*7). Both variants are predicted to trigger nonsense-mediated mRNA decay (NMD), consistent with a loss-of-function mechanism, and parental segregation confirmed asymptomatic heterozygous carrier status, supporting autosomal recessive inheritance. Gene-disease validity assessment assigned a "Strong" classification to FAM149B1-related ciliopathy under ClinGen guidelines, enabling definitive classification of the variants as pathogenic or likely pathogenic. This case expands the phenotypic spectrum of FAM149B1-related disorders to include isolated urinary tract malformations in the prenatal period, where neurological manifestations may be absent or subtle. Our findings highlight the utility of prenatal exome sequencing in atypical cases and contribute to the understanding of the expanding genetic and phenotypic landscape of ciliopathies.

Joubert syndrome (JS) is a rare ciliopathy characterized by neurological and multisystem manifestations; however, skeletal involvement remains poorly recognized. We report two genetically confirmed pediatric patients with JS illustrating different degrees of bone impairment. The first patient, a 2.5-year-old boy with a TMEM67 mutation, presented with severe hypotonia, profound immobility, multiple fractures, and markedly reduced bone mineral density (DXA Z-score -5.875), fulfilling the criteria for secondary osteoporosis and requiring bisphosphonate therapy. The second patient, a 5-year-old girl with an OFD1 mosaic mutation, showed delayed motor development and reduced bone mineral density (DXA Z-score -2.2) without fractures and was managed conservatively. These cases demonstrate the broad spectrum of skeletal manifestations in JS, ranging from low bone mineral density to severe secondary osteoporosis. Reduced mobility and chronic hypotonia may contribute to impaired bone mineralization. Increased awareness and early bone health surveillance, including fracture assessment and densitometric evaluation, may facilitate timely diagnosis and improve management of bone complications in patients with Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a rare, autosomal recessive condition with multisystem manifestations. Sleep disordered breathing (SDB) is a prominent feature, with patients characteristically presenting with a mixture of hyperpnea and apnea. Reports describing whether the respiratory abnormalities change as patients grow older are lacking. METHODS: We describe the clinical course of 21 children with JS followed over 16 years in a tertiary pediatric hospital. RESULTS: Fourteen children underwent polysomnography, while 11 had multiple repeat studies. Patients exhibited a range of SDB, including obstructive sleep apnea which was amenable to conventional treatment. However, obstructive sleep apnoea worsened in one, and central sleep apnea persisted over time. CONCLUSIONS: Children with JS exhibit a range of SDB; however, not all are referred for sleep assessment. Our study contributes to the understanding and awareness of SDB in JS, a population who would benefit from ongoing screening and follow-up polysomnography.

Introduction Joubert syndrome and related disorders (JSRD) are rare and intractable diseases characterized by delayed psychomotor development, hypotonia and/or ataxia, and abnormal respiratory and eye movements. The Patient and Family Advocacy Group for Joubert Syndrome and Related Disorders in Japan was established in 2016. Since its inception, meetings for patients and families have been held approximately once a year. Methods An advocacy group meeting was held at our facility, consisting of a medical lecture and an open forum for information exchange among patients and families. A post-meeting questionnaire was administered to assess the needs and current circumstances of patients and families. Results Many patients were enrolled in or had attended special needs schools or received individualized educational accommodations. All patients had previously received rehabilitation therapy, with a significant proportion continuing therapy at the time of the survey. Families indicated a strong need for information on a range of topics, including medical care, social welfare, and education. Conclusions Addressing the ongoing needs of patients and families with rare and intractable diseases in the areas of healthcare, research, and support system remains a continuing challenge.